Device and method for increasing the transdermal permeation of medicaments

ABSTRACT

The invention relates to a device and a method for increasing the transdermal permeation of medications. The invention is characterized in that a constituent which effects a local increase in temperature and/or an increase in blood flow or the skin is administered in a addition to the transdermally applied active substance.

The invention relates to a device for and to a method of increasing thedermal and/or transdermal permeation of drugs.

The transdermal administration of pharmaceutical active substances hasbeen known from the time of the first commercial use of a scopolaminetransdermal therapeutic system (Scopoderm TTS). Other active substances(nitroglycerine, estradiol, clonidine, isosorbide dinitrate, fentanyl,nicotine, norethisterone etc.) as well are now offered in the form ofsuch a TTS. These active substance patches are adhered to the skin of apatient. The active substance is then released in a controlled mannerfrom the TTS to the skin of the patient, travels through the variouslayers of the skin, and, finally, enters the circulation.

A problem with this mode of administration of a substance having asystemic action is very frequently that the path taken by the activesubstance through the differently constructed layers of the skin is verylong and the transport of the active substance until it enters thecirculation is time-consuming. There are a number of reasons for this.First, the skin possesses a natural barrier function against thepenetration of foreign substances into the body.

Secondly, substances having a very large molecular radius possess only alow diffusion coefficient. The latter is a measure of the ability of asubstance to travel within a medium; in the case in hand, therefore, thepermeation behavior within the skin layers. And, finally,physico-chemical interactions (for example, polar interactions,dipole-dipole interactions, etc.) between the active substance and thevarious constituents of the different skin layers may lower the rate ofdiffusion of an active substance in the skin.

All of these phenomena may result in the percutaneous and subsequentabsorption of the active substance taking place so slowly that apharmacological effect occurs only with considerable time delay. Thisperiod between the application of a TTS to the skin of the patient andthe onset of the pharmacological effect is referred to by the skilledworker as the lag time.

Almost logically, therefore, enhancing the percutaneous permeation of atransdermally administerable active substance has been the subject ofextensive research work, especially by the pharmaceutical industry. Ithas led to the use of a very wide variety of substances which improveskin penetration (known as enhancers) and to the development of specificsubstances, e.g., Azone®. Enhancers include alcohols, amides, aminoacids, derivatives of Azone®, essential oils, fatty acids and fatty acidderivatives such as fatty acid esters, macrocyclic compounds,phospholipids, pyrrolidones, sulfoxides, and others.

When such enhancers are given, the increase in skin penetration (or,more precisely, the acceleration of an active substance's entry into andtravel through the various skin layers and thus, ultimately, the raisingof the transdermal absorption rate as well) is essentially achieved byvirtue of the fact that these enhancers penetrate the uppermost layersof the skin, where they alter the structure of the skin in such a waythat its barrier function is no longer fully effective. This mode ofaction is explained at the molecular level as follows: the enhancersincorporate themselves into biological membranes and alter the naturalstructure of lipids and proteins—causing them, for example, to swell.The active substance applied to the skin is then able to travel moreeasily, i.e., more quickly, through the different layers of the skin.

The use of the prior art enhancers, however, also possesses manydisadvantages. First of all, the enhancer must not be toxic and must notcause any physiological side effects. Further, there must be no chemicalor physical incompatibilities between enhancer and both the activesubstance and the other materials constituting the TTS. Finally, theenhancer must be present in the TTS in an amount such that thepermeation-intensifying effect is retained over the entire period of itsapplication (generally from 16 to 24 hours, although there are also3-day plasters already available). An inevitable result of this,however, is often that said enhancer is administered to the patientlikewise in amounts such as to cause a systemic effect.

It is an object of the present invention to accelerate the penetrationof an active substance into the skin and/or the travel of this activesubstance through the different layers of the skin and/or the transportof this active substance through the blood capillary system of thedermis and/or the blood vessels of the hypodermis in such a way thatabsorption through the skin takes place more rapidly and thus areduction in the lag time is achieved. In particular, practicaltransdermal application should be made accessible to active substanceswhich by their nature exhibit a long lag time for absorption through theskin.

This object is achieved by a device which comprises a component whichbrings about a local temperature increase in the skin and/or increasesthe circulation. The device of the invention can be, for example, anointment, a solution, a suspension, an emulsion, a foam, a paste, a gelor a patch, a patch of this kind being a preferred embodiment.

The invention further provides a method which comprises achieving anincrease in the rate of penetration of an active substance into the skinand/or of travel of this active substance through the different layersof the skin and/or of transport of this active substance through theblood capillary system of the dermis and/or the blood vessels of thehypodermis by means of a local temperature increase and/or an increasein the circulation of the skin. In this way, ultimately, the transdermalabsorption rate of said active substance is increased and the lag timeto the onset of a pharmacological effect of said active substance isreduced.

The use of substances which bring about a local temperature increase inthe skin for the purpose of increasing the rate of penetration of anactive substance into the skin and/or of travel of this active substancethrough the different layers of the skin and/or of transport of thisactive substance through the blood capillary system of the dermis and/orthe blood vessels of the hypodermis is likewise provided by the presentinvention. It is possible to achieve either a short-term effect (thatis, up to the onset of the pharmacological effect) or a long-term effect(that is, throughout the duration of transdermal administration of theactive substance in question).

Further elucidation of the invention is aided by the followingdefinitions:

Skin refers to the uninjured, i.e., undamaged, unshaved skin of amammal, especially that of a human, said skin having its normal haircover. For the purposes of this invention, the term skin does notinclude mucous membrane. Normal skin consists essentially of threelayers: the epidermis (situated externally), the dermis, and thehypodermis (which is situated below). The hypodermis is also referred toas the subcutis. The epidermis in turn is composed of the stratumcorneum, stratum lucidum, stratum granulosum, stratum spinosum andstratum germativum. The dermis contains, inter alia, the blood capillarysystem. The hypodermis houses the blood vessels.

Penetration refers to the penetration of an active substance into theouter layers of the skin, especially into those of the epidermis.Permeation refers to the travel of the active substance through theskin, especially through the epidermis (including the stratum corneum)and the dermis.

The term dermal administration as used in the present description meansthat an active substance is applied to the skin and develops a local orregional (i.e., topical) action in the epidermis and/or dermis.Transdermal administration in the present description means that anactive substance is applied to the skin, passes through the epidermisand/or dermis into the blood stream or into the lymph system, isdistributed from there throughout the body, and develops a systemicaction at the target site. Transdermal absorption is used to denote thetakeup of an active substance by the under-skin blood vessels followingtransdermal administration, thereby permitting a systemic action of theactive substance taken up.

Active substances for the purposes of the present invention areessentially pharmaceutical and/or cosmetic active substances which serveto prevent, alleviate, heal or reveal disorders. They include substanceswhich are able to exert a topical and/or systemic action. Activesubstances are known to the skilled worker and can be found in standardworks, such as, for example, the German “Red List” (pharmaceuticalactive substances) and “Green List” (cosmetic active substances).Further active substances are specified in U.S. Pat. No. 4,557,934 andin the sources cited therein (col. 10, lines 18-35). In order to avoidrepetition, the content of that patent insofar as it refers to activesubstances is considered part of the disclosure of the present inventionby reference. In principle, the nature of the active substance is notcritical to the present invention. The term active substance shouldtherefore not be interpreted in a manner which restricts the subjectmatter of the invention.

Active substances which by their nature exhibit a long lag time onabsorption through the skin include the following: opiates such as, forexample, morphine, diamorphine, buprenorphine; fentanyl, estrogens suchas, for example, 17β-estradiol; hormones such as, for example,testosterone, norethisterone, gestagens; peptides such as, for example,insulin;

analgesics; and alkaloids. This type of systemic active substance can bemade amenable to transdermal administration in a particularlyadvantageous way by means of the-subject matter of the invention.

The component which brings about a local temperature increase and/or anincrease in the circulation of the skin is a substance or substancemixture which when applied to the skin results in local heating of theskin. Such substances include especially rubefacientia, vasodilators,and hyperemic substances.

Rubefacientia are substances which as a consequence of hyperemia have askin irritant and/or skin reddening action. Rubefacientia are thereforea particular group of hyperemic substances. They include, for example,pelargonic acid vanillyl amide, cayenne pepper oil resin, capsicumextract, capsicum tincture, cayenne pepper extract, cayenne pepper, andcapsaicin.

Vasodilators are vessel widening substances which bring about a wideningof the blood vessels by, for example, relaxing the vessel musculature.This is often accompanied by a lowering of blood pressure. This alsotakes place, of course, in the peripheral blood vessels, so producingincreased blood flow through the area affected. Vasodilators includenicotinic acid; derivatives of nicotinic acid such as, for example,nicotinyl alcohol, benzyl nicotinate, nicotinamide, etc.; adenosinecompounds; xanthine, derivatives of xanthine such as caffeine, etc.;arnica extract, arnica blossom extract, pyridyl-3-carbinol and itssalts, camomile, phytolacca, guaia gum, cinnabaris, creosotum, Luffaoperculata, and tincture of Rhus toxicodendron.

Hyperemic substances are substances which increase circulation. Theincrease in circulation is brought about by increased blood afflux(reactive hyperemia) or reduced blood efflux (restriction hyperemia).This can have various causes. Hyperemic substances include essentialoils, menthol, camphor, nicotinic esters, salicylic esters, hydroxyethylsalicylate, methyl salicylate, and ortho-carbamoylphenoxyacetic acid.

The heat effect in the skin is, therefore, brought about essentially byan improvement in the circulation to the peripheral blood vessels(capillary system). It is not based on a heat effect in the form, forexample, of thermal conduction, ultrasound, thermal radiation, etc.,being exerted on the skin from the outside. There is no transport ofenergy from an external energy source into the skin.

Devices of the abovementioned kind are produced in a known manner wherethe device in question is an ointment, solution, suspension, emulsion,foam, paste, aerosol, or gel. All that must be done is to incorporatethe component which brings about a local temperature increase in theskin into the active substance composition in an appropriate processstep. Said ointment, solution, suspension, emulsion, foam, paste,aerosol or gel can be applied to the skin area in question directlyprior to application of the active substance ITTS. It can also beapplied to the skin around the TTS following application of the latter.

Owing to the difficulty in controlling the amount applied in this caseof the component which brings about a local temperature increase of theskin, and owing to any concomitant adhesion problems of the TTS on theskin, the preferred embodiment is, as stated, a patch.

A patch of this kind, i.e., a dermal or transdermal therapeutic system,can comprise the following structural elements: an active substanceimpermeable backing layer, an active substance reservoir, an activesubstance release controlling (semipermeable or microporous) membrane,an adhesive layer containing active substance, and a redetachableprotective layer (known as the release liner).

In accordance with the invention, the component which brings about alocal temperature increase and/or circulation increase in the skin canbe present in the active substance reservoir and/or in the adhesivelayer containing active substance. Alternatively, in order to avoidincompatibilities but also as a preferred embodiment, the componentwhich brings about a local temperature increase of the skin can also bepresent in a structural element of the device which is spatiallyseparate from the structural elements containing active substance.

The simplest embodiment of this case is a pressure sensitive adhesivelayer which comprises the component that brings about a localtemperature increase and/or increase in circulation in the skin andwhich is equipped with a backing layer impermeable to said component. Inthis embodiment, the device consists of two separate devices, namely anactive substance release device and the device containing the componentwhich brings about a local temperature increase and/or circulationincrease in the skin. The active substance release device, an activesubstance TTS for example, is applied first of all to the skin of thepatient. Then the device containing the component which brings about alocal temperature increase of the skin is placed atop it and judiciallyfixed—for example, by means of a pressure sensitive adhesive layerlocated on the bottom, pressure sensitive adhesive strips located on theedge of the device, or a further, cover patch. Likewise preferred is anembodiment in which an outer segment containing the component whichbrings about a local temperature increase and/or circulation increase inthe skin is disposed around an inner segment which contains the activesubstance intended for transdermal administration. The form of the innersegment is in principle not critical; it can be circular, rectangular orsquare. The form of the outer segment is likewise in principle notcritical; it can also be circular, rectangular or square. Alternatively,the outer segment can be disposed around the inner segment in the formof a ring or as two or more sections which are, for example, rectangularor semicircular. This embodiment is particularly suitable since itprofits from the formation of a horizontal concentration gradient in theepidermis and in the dermis/subcutis. Although this so-called lateraldiffusion can be derived from the structure of the stratum corneum withits lamellar lipid-water bilayers, this phenomenon has, surprisingly, todate not been considered by those skilled in the art for a practicalimplementation in terms of increasing the rate of penetration into theskin and/or of travel through the skin, in particular for increasing thetransdermal absorption rate of an active substance applied to the skin.

In this advantageous embodiment, the outer segment overhangs the innersegment to a considerable extent; for example, by several millimeters(e.g.: from 5 to 25) or by the length of the diameter of the innersegment. In this way, the principle responsible for the increase in thetransdermal absorption rate of the active substance acts on an areawhich projects beyond the mere release area of the transdermallyadministered active substance.

The area of the pressure sensitive adhesive layer, or of the outersegment, which contains the component which brings about a localtemperature increase and/or increase in the circulation of the skin isgenerally smaller than 100 cm².

A preferred embodiment of this kind can likewise be produced byprocesses known to the skilled worker, as described, for example, in DE37 14 140, DE 38 09 978 and DE 41 10 027. In order to avoid repetition,the relevant section of the disclosure contents of these documents hasnot been reproduced here but is considered to be incorporated byreference. It is clear that when producing the outer segment thecomponent which brings about a local temperature increase of the skinmust be incorporated into the matrix forming the outer segment, in theappropriate working step. The spatial separation of the segmentscontaining the component which brings about a local temperature increaseand/or circulation increase in the skin from the segments containing theactive substance intended for transdermal administration is achieved byhorizontal or vertical barrier layers or material voids.

Depending on the amount of the component which brings about a localtemperature increase and/or circulation increase in the skin, the actionof the device of the invention may extend over a relatively long period:for example, about 8, 16, 24, 48 or even 72 hours. The device of theinvention is applied to the skin of the patient under normal conditions,i.e., at normal—that is, not increased—external skin temperature.Alternatively, the device of the invention can be applied before andduring an iontophoresis treatment.

Within the device, the amount of the substance which is able to bringabout a local temperature increase and/or circulation increase in theskin depends on whether the desire is for a short-term effect, until theonset of the pharmacological effect, or a long-term effect, throughoutthe duration of the transdermal administration of the active substancein question.

It is also guided in each specific case by the specific properties ofthe substance. In general, therefore, the amount of this substancewithin the device is between 0.5 and 20% by weight.

The device of the invention is preferably free from permeationenhancers, i.e., substances which by intervening in the structure of theskin achieve an improvement in the skin permeation of a dermallyadministered active substance, but may, if desired, comprise suchsubstances. A list of these substances can be found from the article byD. W. Osborne and J. J. Hill on “Skin penetration enhancers cited in thetechnical literature” on the Internet websitehttp://pharmtech.com/technical/osborne/osborne.htm.

The examples which follow serve to elucidate the mode of action of theinvention.

EXAMPLE 1

Three samples of a commercially available estradiol active substancepatch (Vivelle®) were each applied centrally to circular specimens ofcomplete human skin, measuring 4.52 cm² . The skin samples thus preparedwere placed for 72 h in modified Franz cells, there being no acceptormedium, so as to avoid artefacts as a result of back-diffusion into thecells. After the end of this time, the active substance patches wereremoved and the skin below the application site was punched out exactly.Further circular segments were punched out from the skin sample, eachsituated further and further from the core segment, that is, the actualrelease area of the TTS.

The skin samples obtained in this way were subsequently extracted withmethanol for 16 h and assayed for residual estradiol. A horizontalconcentration profile was found which was also statisticallysignificant. The results of the residue assay are given in Table 1. Thehorizontal concentration profile found is reproduced in FIG. 4.

TABLE 1 Skin segment R1 R2 R3 R4 Residual content in μg/cm² 8.62 5.160.23 0.06 Key: R1 = skin segment directly below the TTS application area(=1.13 cm²) R2 = 1st skin segment outside the TTS core segment (=1.41cm²) R3 = 2nd skin segment outside the TTS core segment (=1.98 cm²) R4 =3rd skin segment outside the TTS core segment (=2.54 cm²)

EXAMPLE 2

An in vivo animal experiment was performed on two groups of rats eachcontaining n=6 animals. Each of the animals from both groups had adheredto it a TTS containing a poorly absorbable active substance (morphinebase). In the animals of the first experimental group, a cover patchcontaining an effective amount of a component which brings about a localtemperature increase of the skin (ABC patches from Beiersdorf, Hamburg(DE)) was applied over the actual active substance release TTS. Theeffective substances of said cover patch are capsaicin and arnicaextract. The areal skin contact of the cover patch in comparison to thatof the active substance release TTS was 3 to 1.

The animals of the second experimental group (the control group)received as cover patch a self-adhesive occlusive film without acomponent which brings about a local temperature increase of the skin(Opraflex from Lohmann, Neuwied (DE)). The areal skin contact of thecover patch in comparison to that of the active substance release TTSwas likewise 3 to 1.

After the end of the 24-hour period of wear, the patch dressings wereremoved and were assayed for residues of morphine base. The results aresummarized in Table 2 and show that the use of a cover patch containingan effective amount of a component which brings about a localtemperature increase of the skin increased the transdermal absorptionrate from 5.7 to 26.4%.

TABLE 2 Experimental group with Opraflex cover patch TTS Initial amountResidue Released Verum 1 546.7 μg/cm² 506.6 μg/cm² 40.1 μg/cm² Verum 2546.7 μg/cm² 514.2 μg/cm² 32.5 μg/cm² Verum 3 546.7 μg/cm² 538.8 μg/cm² 7.9 μg/cm² Verum 4 546.7 μg/cm² 528.0 μg/cm² 18.7 μg/cm² Verum 5 546.7μg/cm² 494.9 μg/cm² 51.8 μg/cm² Verum 6 546.7 μg/cm² 510.0 μg/cm² 36.7μg/cm² Mean: 515.4 μg/cm² 31.3 μg/cm²

This gives a relative absorption rate of 5.72%.

Experimental group with ABC-Wärme-Pflaster N cover patch TTS Initialamount Residue Released Verum 1 546.7 μg/cm² 364.7 μg/cm² 182.0 μg/cm²Verum 2 546.7 μg/cm² 354.6 μg/cm² 192.1 μg/cm² Verum 3 546.7 μg/cm²442.9 μg/cm² 103.8 μg/cm² Verum 4 546.7 μg/cm² 447.9 μg/cm²  98.8 μg/cm²Verum 5 546.7 μg/cm² 446.8 μg/cm²  99.9 μg/cm² Verum 6 546.7 μg/cm²359.0 μg/cm² 187.7 μg/cm² Mean: 402.7 μg/cm² 144.1 μg/cm²

This gives a relative absorption rate of 26.4%.

This result is all the more surprising since this method of improvingthe permeation of a transdermally administerable active substancethrough the skin is neither a chemical nor another invasive processwhich permanently damages the skin. Therefore, there is no interventionin the structure of the skin, especially the epidermis, and so neitheris there any need to activate the “self-repair” mechanism of the skin.

On the basis of a local temperature increase and/or circulation increaseof the skin, therefore, the device and the method bring about anincrease in the rate of penetration into the skin and/or an increase inthe travel through the skin and/or an increase in the transdermalabsorption rate of an active substance applied to the skin.

Embodiments of the invention are elucidated using FIGS. 1 to 4.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an embodiment in which the component which brings about alocal temperature increase and/or circulation increase in the skin ispresent in the same reservoir and in the same pressure sensitiveadhesive layer as the active substance intended for transdermaladministration. The reference symbols have the following meanings:11=skin, 12=active substance impermeable backing layer, 13=reservoircontaining the active substance intended for transdermal administrationand, if appropriate, the component which brings about a localtemperature increase and/or circulation increase in the skin,14=semipermeable or microporous membrane for controlling activesubstance release, 15=pressure sensitive adhesive layer containing theactive substance intended for transdermal administration and thecomponent which brings about a local temperature increase and/orcirculation increase in the skin.

FIG. 2 shows an embodiment in which the component which brings about alocal temperature increase and/or circulation increase in the skin isspatially separated by a vertical barrier layer from the reservoir andfrom the pressure sensitive adhesive layer containing the activesubstance intended for transdermal administration. The reference symbolshave the following meanings: 21=active substance impermeable backinglayer, 22=reservoir containing the active substance intended fortransdermal application but free from the component which brings about alocal temperature increase and/or circulation increase in the skin,23=pressure sensitive adhesive layer containing the active substanceintended for transdermal administration but free from the componentwhich brings abouta local temperature increase and/or circulationincrease in the skin, 24=pressure sensitive adhesive layer containingthe component which brings about a local temperature increase and/orcirculation increase in the skin, 25=vertical barrier layer.

FIG. 3 shows an embodiment in which the component which brings about alocal temperature increase and/or circulation increase in the skin isspatially separated by a horizontal barrier layer from the reservoir andfrom the pressure sensitive adhesive layer containing the activesubstance intended for transdermal administration. The reference symbolshave the following meanings: 31=active substance impermeable backinglayer, 32=reservoir or pressure sensitive adhesive layer containing theactive substance intended for transdermal administration but free fromthe component which brings about a local temperature increase and/orcirculation increase in the skin, 33=pressure sensitive adhesive layercontaining the component which brings about a local temperature increaseand/or circulation increase in the skin, 34=horizontal barrier layer,35=skin.

FIG. 4 depicts the horizontal concentration profile discussed in Example1.

What is claimed is:
 1. A device having a layered construction fortransdermal administration of at least one active substance to asubject, said device comprising: (a) a first layer comprising at leastone active substance selected from the group consisting ofpharmaceutically and cosmetically active substances, and (b) a secondlayer comprising at least one component that causes an increase in localtemperature and/or blood circulation in the skin where said component isrubefacient which comprises pelargonic acid vanillyl amide, cayennepepper oil resin, capsicum fruit extract, tincture of capsicum extract,cayenne pepper, or a combination of the foregoing, wherein the devicecontains an amount of said component effective to increase the rate ofpenetration of active substance(s) into the skin, the movement of activesubstance(s) through the skin and/or the transdermal absorption rate ofsaid active substance(s) applied to the skin and wherein the first layeris spacially separated from the second layer.
 2. The device as claimedin claim 1, which further comprises a backing layer that is impermeableto said component or that prevents emergence of said component on theside facing away from the skin.
 3. The device as claimed in claim 1,which further comprises a pressure sensitive adhesive layer that extendsover the full area of the bottom side of the device or that is locatedonly- at the edge of the bottom side of the device.
 4. The device asclaimed in claim 1, wherein at least one horizontal barrier layer, atleast one vertical barrier layer, at least one gap in the materialand/or a mixture of the foregoing is used to-separate spatially thefirst layer from the second layer.
 5. The device as claimed in claim 1,wherein the pharmaceutically and/or cosmetically active substancepossesses a systemic or topical action.
 6. A method of enhancing thepercutaneous permeation of a transdermally administrable activesubstance in a subject which comprises a) applying to a site of the skinin the subject a device comprising a component which causes an increasein temperature in blood and/or circulation in the local area of thesite, thereby effecting a localized temperature increase in said site ofthe skin, and b) applying said active substance to said site of theskin, whereby said temperature increase in said site of the skin issufficient to increase the rate of penetration of active substance(s),the movement of active substance(s) through the skin, and thetransdermal absorption rate of active substance(s) applied to the skin.7. The method according to claim 6, wherein the temperature increase isa short-term effect which lasts until the onset of the pharmacologicaleffect of said active substance(s).
 8. The method according to claim 6,whereas the temperature increase is a long-term effect throughout theduration of transdermal administration of said active substance(s). 9.The method according to claim 6, whereas the device comprising saidcomponent is selected from the group consisting of an ointment, asolution, a suspension, an emulsion, a foam, a paste, a gel or a patch.10. The device as claimed in claim 1, wherein the pharmaceuticallyactive substance is morphine, diamorphine, buprenorphine, fentanyl,17β-estradiol, testosterone, norethisterone, or insulin.
 11. The deviceaccording to claim 1, which does not comprise a permeation enhancer. 12.The device according to claim 1, which further comprises at least oneadditional permeation enhancer.